Osteoporosis is the most common metabolic bone disease affecting more than 10 million Americans, nearly 50% of the elderly female and more than 10% of the elderly male population. (Rachner, T. D.; et al. Lancet 2011, 377, 1276-1287. Silva, B. C. Annu. Rev. Med. 2011 62, 307-322. Lyritis, G. P; et al. Ann. N. Y. Acad. Sci. 2010, 1205, 277-283. Khosla, S.; et al. J. Clin. Endocrinol, Metab. 2012, 97, 2272-2282. Aspray, T. J.; et al. Maturitas 2012, 71, 76-78. Black, D. M.; et al. N. Engl. J. Med. 2012, 366, 2051-2053.) Osteopenia (reduced bone mass), a major risk factor for developing osteoporosis, is even more common, affecting 34 million Americans. Bone fractures are a widespread complication of osteoporosis and osteopenia resulting in significant socio-economic cost, such as hospitalization and disability, and very often they are the cause of deterioration and death of otherwise healthy and functioning elderly individuals. Age-related osteoporotic bone loss and its resulting complications cause significant morbidity and mortality in the aging population.
Bone health in adult life depends on a coordinated balance of anabolic and catabolic cellular activities of bone-forming osteoblasts and bone-resorbing osteoclasts, respectively. Multipotent mesenchymal stem cells (aka marrow stromal cells, MSCs) form the precursor population for a variety of cell types, including osteoblasts and adipocytes. Formation of new bone is driven by osteoblastic differentiation of MSCs, a process that can be disrupted by a number of factors. Aging, disease and lifestyle factors such as tobacco and alcohol abuse tend to push MSC populations toward adipogenesis at the expense of osteoblast differentiation, resulting in osteopenic disorders that often lead to full-fledged osteoporosis and impaired fracture repair. The mechanisms behind lineage-specific differentiation of MSC can be important. Factors can stimulate osteoblast formation while inhibiting adipogenesis.
Among two possible therapeutic strategies for osteoporosis, prevention of bone loss/resorption or stimulation of bone growth, anti-resorptive therapy with bisphosphonate drugs is more established. (Khosla, S.; et al. J. Clin. Endocrinol. Metab. 2012, 97, 2272-2282 Sharpe, M.; Noble, S.; Spencer, C. M. Drugs. 2001, 61, 999-1039.) Nearly all current therapies for osteoporosis as well as the majority of potential new treatments under clinical investigation aim to reduce the level of bone resorption in osteoporotic patients. Therapies on the market or in clinical trials that target mechanisms of bone resorption include Denosumab (Prolia), Zolendronic Acid (Reclast), Odanacatib, and Saracatinib. Anti-resorptive drug therapy has been most effective in treating early and mild cases of the disease, unlike advanced osteoporosis where a massive loss of bone mineral density has already occurred.
Alternatively, bone anabolic agents can provide additional treatment options, particularly with advanced disease, and significantly improve osteoporosis management, in spite of a paucity of FDA approved drugs in this area. Currently, the only FDA approved bone anabolic agent available for treatment of severely osteoporotic patients is teriparatide (Forteo), a recombinant form of parathyroid hormone (PTH), which has to be administered intermittently, by daily injection. Forteo can produce significant bone formation and reduce fracture risk, but its use is severely restricted due to safety concerns. Due to adverse side effects, such as an increased risk of osteosarcoma, drug labeling for Forteo is highly restricted with respect to patient population and duration of use (less than 24 months). (Cosman, F.; et al. Curr. Osteoporos. Rep. 2014, 12, 385-395. Muschitz, C.; et al. J. Bone Miner. Res. 2013, 28, 196-205. Vescini, F.; et al. Clin. Cases Miner. Bone Metab. 2012, 9, 31-36.) Other anabolic agents under clinical investigation include calcilytic drugs that stimulate endogenous intermittent PTH secretion, antibodies to an inhibitor of osteoblasts called Sclerostin, and inhibitors of antagonists of Wnt signaling. (Silva, B. C.; et al. Annu. Rev. Med. 2011 62, 307-322)
In patients with mild osteoporosis, bisphosphonate drugs (e.g., alendronic acid, Fosamax) can produce significant benefits such as improved bone density and reduced fracture risk. However, bisphosphonate drugs, including alendronic acid, display low oral bioavailability, 0.6-0.7% on average, even when ingested under fasting conditions. Drug intake together with meals and beverages (other than water) further reduces the bioavailability, and intake under fasting conditions entails serious upper GI tract irritation in a majority of patients. Hence, repeated, often daily, oral dosing under fasting conditions is necessary to maximize delivery of the bisphosphonate drugs to what is pharmacologically achievable while more than 99% of the dose cannot be absorbed and is ejected from the body unused. The fraction of bisphosphonate drug that can be absorbed, can rapidly partition in the human body, with about 50% of the drug binding to bone surface and the rest being excreted unchanged via the kidneys. The physicochemical basis of low oral absorption is thought to be associated with the negatively charged phosphonate moieties that are unavoidably part of all bisphosphonate drugs. To overcome this drawback, strategies have been investigated, including prodrug approaches with fatty acid and bile acid conjugation that aim to mask the phosphonate charge effect. (Bortolini, O.; et al. Euro. J. Med. Chem. 2012, 52, 221-229. Vachal, P.; et al. J. Med. Chem, 2006, 49, 3060-3063.)
Naturally-occurring oxysterols can act as drug-like molecules with an effect on MSCs and other multipotent mesenchymal cells. Oxysterols that occur in human circulation and various tissues can be short-lived intermediates in metabolic transformations of cholesterol to form steroid hormones and bile acids. Beyond their role as passive metabolites, however, natural oxysterols can function as signaling molecules, capable of modulating a range of physiological phenomena, among them homeostasis of lipids as well as control over cellular states such as differentiation, inflammation and apoptosis. That is, oxysterols can play a role as regulators of tissue specific signaling. Early research on oxysterols considered their pathological contributions and assumed that all oxysterols have similar properties, regardless of their distinct chemical composition. Oxysterol chemotypes can have more individualized characteristics that depend on the cellular context and the exact chemical composition of the oxysterol. (Schroepfer, G. J. Physiol. Rev. 2000, 80, 362-554. Gill, S.; et al. Prog. Lipid Res. 2008, 47, 391-404. Sottero, B.; et al. Curr. Top. Med. Chem. 2009, 16, 685-705.) Some oxysterols can promote oxidative stress. However, osteogenic oxysterols can inhibit the adverse effects of oxidative stress on osteogenic differentiation of progenitor cells. Some oxysterols are thought to be endogenous ligands of Liver X Receptors (LXR). However, the osteogenic activity of oxysterols may not be a consequence of LXR activation, but can be mediated through the activation of Hh signaling. The oxysterol-induced activation of Hh signaling can occur independent of Hh proteins and result in the activation of non-canonical Wnt and Notch signaling. Baseline PKA/cAMP, PKC, MAPK, and PI3-Kinase signaling can be involved in mediating various aspects of the cellular responses to these oxysterols. (Kha, H. T.; et al. J. Bone Miner. Res. 2004, 19, 830-840. Richardson, J. A.; et al. J. Cell. Biochem. 2007, 100, 1131-1145.) In spite of reported cytotoxicity of some oxysterols, no toxic effects were found with osteogenic oxysterols in vitro when dosed at 1-20 μM with osteoprogenitor cells or, in vivo, during local administration in the rat spine fusion model (40 mg), or, in mice, dosed ip at 50 mg/kg 3 times per week for a total of 8 weeks as determined by the absence of behavioral changes.